Keratoconus: A Treatable Disease

*Gustavo E. Tamayo, Eduardo J. Polania-Baron, Claudia Castell, Pilar Vargas and Juliana Tamayo*

### **Abstract**

Keratoconus is a very frequent disease and is no diagnosed in many cases. Our chapter will focus on the several diagnostic tools not to miss this disease and also will present a all the treatment options with special focus on Corneal Cross Linking. All the indications for this treatment will be analyzed and extensively discussed as it should be considered the only option to stop the progress of the cone. Also, statistical analysis from our clinic with more than 2000 treatments with Cross Linking and follow up since 2006 will be presented. Literature review with results of this treatment is also going to be presented. Finally, a case of keratoconus treated with PRK and follow up of 30 years will be discussed and analyzed as the introduction of the combination of Cross Linking and Wavefront as one very good option in cases of mild to moderate keratoconus.

**Keywords:** ectasia, crosslinking, eye rubbing

### **1. Introduction**

Keratoconus is a disease of the cornea characterized by focal thinning and protrusion, with clinical manifestation of astigmatism, either regular when the disease is not well developed, or irregular astigmatism in severe cases. The condition is usually bilateral, although almost always asymmetrical. Due to its lack of neovascularization and cellular infiltration, it is defined as a non-inflammatory disorder [1]. However, association between atopy, ocular allergic disease, eye rubbing, high levels of serum immunoglobulin E, enzymatic alterations [2–4], alterations in interleukin (IL)-1 receptors density [5, 6], and keratoconus exists [7–10]. Nonetheless, it is important to say that in a case-control study a multivariate analysis found that only eye rubbing was still a significant predictor of keratoconus [11]. More recent studies have proved that there is a significant action of inflammatory mediators and a possible effect of oxidative stress, thus questioning the non-inflammatory status of the disease [12–15].

Eye rubbing is certainly a very important factor in the production of keratoconus as demonstrated in the frequency of this disease in populations such as patients with Down Syndrome [16]. It is also commonly associated with allergic diseases of the eye, and it has also been associated with a rub of the cornea against the pillow when sleeping. In any case, keratoconus appears early in life (preadolescence), and usually progresses until 25–30 years of age. Of course, there are some reports of cases in an older age, as well as keratoconus in infants [17, 18].

### **2. Epidemiology**

Keratoconus epidemiology varies in every country and even in different populations within the same country. There are report of 6/1000 and up to 50–230 per 100,000 [19]. Other studies in Asia show a prevalence ranging from 0.3 per 100,000 people to 25% prevalence [20, 21]. A recent review in the Netherlands published in the year 2017, shows an annual incidence of keratoconus of 1:7500 in people between 10 and 40 years-old (13.3 cases per 100,000, 95% confidence interval [CI]: 11.6–15.2) with a prevalence of 1:375 (265 cases per 100,000, 95% CI: 260–270) [22].

### **3. Treatment of keratoconus: history**

Traditionally, only two options were available for the treatment of keratoconus. From a medical point of view, hard contact lenses gained popularity as a method in stopping the progression of the disease. The only surgical option to correct this condition in patients with intolerance to contact lenses was penetrating corneal transplant, a high-risk procedure for such a young patient. In 1991, intrastromal corneal rings were introduced as a way to correct myopia [23, 24]. Later on, they began being used for treatment of keratoconus and corneal ectasias, and today, they are the only indication for ICRS [25, 26].

In 1997 [27], one of us (GT), started to treat mild to moderate keratoconus with PRK under the theory that the scar tissue formed in the intersection of the Bowman's membrane and the stroma would stop the progression of the disease. This concept was criticized by many but also accepted by others. Studies presented in several meetings by GT, analyzing their own cases, showed that after 12 years of follow up, 50 eyes treated with PRK alone without Cross Linking (not available by that time), 4 eyes did not improve and required Corneal Transplant, accounting for 8% of the cases. That is considered an excellent result, since reports of untreated keratoconus vary from 10% to even 60% of corneal transplant [28, 29].

We also present the history in 1999 of a 22-year-old male who was sent to our clinic looking for a corneal transplant. Considering the theory of the scar tissue after excimer laser, we decided to perform a PRK instead and today, after more than 25 years of follow up, is still stable and with an excellent visual acuity. In his last visit, he had a refraction in his right eye of +0.75–2.25 × 15 and a BCVA of 20/20 and in his left of +0.75–2.00 × 150 and a BCVA of 20/20. Topography stability could be seen in **Figure 1**. With this patient, along with the success in selected cases of keratoconus treated with PRK, there is the idea of considering this as a treatable disease.

22 years ago (year 1999) Corneal Crosslinking was introduced as an option to halt keratoconus progression, and it was first described by Spoerl et al., using 254 nm ultraviolet light and riboflavin in dextran [30]. Vitamin B2 is important to control UV-light penetration in the cornea and to avoid endothelial and inner eye damages. Details regarding osmolarity are crucial because corneal thinning or corneal swelling can be achieved by using hyperosmolar or hypo-osmolar riboflavin, respectively [31, 32]. And studies reveal that the stronger effect of UV-light absorption, and in consequence crosslinking effect, occurs in the anterior stroma (anterior 252 μm) [33–36] where keratocyte apoptosis and repopulation (after 6 months of CXL) is more evident [37, 38]. Other studies have shown an increase in type I collagen fibers diameters after corneal crosslinking, and this effect causes not only intrafibrillar but also interfibrillar crosslinking and these changes could be seen in a greater way at the anterior stroma [37, 39].

### *Keratoconus: A Treatable Disease DOI: http://dx.doi.org/10.5772/intechopen.101206*

### **Figure 1.**

*Corneal topography follow-up (year 2011–2017) of one of our oldest patients who is 36 years old, he had PRK surgery at age 22 instead of a corneal transplant. Corneal topography shows keratometric and pachymetry stability in the right eye (upper maps) and in the left eye (lower maps).*

Eighteen years ago the first clinical study of corneal crosslinking was performed by Wollensak et al. [40]. There is significant evidence in the literature to support the use of corneal crosslinking to halt its progression, and in a few cases, a second treatment may be required [41–45].

The development of Cross Linking revitalized our idea to treat keratoconus and gave those patients the freedom of hard contact lenses, the only option before a corneal transplant for these patients. Cross Linking appeared as the only minimally invasive procedure able to stop the progression of this disease, and is considered the gold standard to halt the progression of keratoconus [46, 47]. According to the Global Consensus of Keratoconus and Ectatic Diseases published in 2015, currently 83.3% of ophthalmic physicians are performing CXL as a treatment modality for keratoconus and all the physicians who do not currently have access to this technique are willing to use this procedure once it becomes available [48].

It has been proven that crosslinking not only halts progression but improves topographic, refractive, and visual acuity parameters [49–53] (UCDVA, BCVA). Although it is important to say that there are some case reports of loss of UCDVA and BCDVA lines after crosslinking [54, 55].

The pediatric population is the center of any health specialty. In our field, it is important to detect keratoconus in these patients, mainly to prevent a corneal transplant in the future. It is also important to prevent eye rubbing, and if there is any detection of topographic progression, to perform a corneal crosslinking without hesitation. Many clinical studies support the use of crosslinking in this special population, where topographic corneal parameters show stability or even improvement [56–59]. Some studies illustrate adverse effects such as worsening of topographic or pachymetry changes in the same group [60, 61]. However, the general consensus is that there is a beneficial effect in young patients with a progressive keratoconus [62], and it has been advocated that those changes are due to the natural history of the disease rather than effect of the Cross Linking itself.

There are also several studies showing the advantage of combining KXL with other refractive procedures, such as intrastromal rings, or intraocular lenses, or Excimer Laser in PRK, or surface ablation form. These combinations not only halt the progression of the keratoconus but also help with vision, decreasing the refractive defect.

In our practice, we reviewed 50 cases of patients under 16 years of age with more than 5 years of follow up and found only one patient (2%) in whom the keratoconus progressed and needed a second successful application of accelerated Cross Linking a year later. These were patients with KXL as the only treatment without any combination. One example of a 6 years old girl with 9 years follow up is presented here. It is important to mention that the girl was the daughter of a woman with corneal transplants for keratoconus and the granddaughter of a woman with two corneal transplants as well. The progression of the keratoconus was documented from the age of 5–6. No repetition of the Cross Linking has been needed. Pictures of this pediatric patient are presented in **Figure 2**.

We have advocated the possibility to combine Cross Linking with Intrastromal Rings. In fact, today we consider a protocol to place rings and combine them with Cross Linking, and we strongly suggest to never implant rings without this combination, since this assures a halt in the progression of the cone. At the same time, it enhances the effect of the rings. In our clinic, we reviewed 84 eyes treated with Intrastromal rings implanted with Phemtosecond technique and combined with KXL in the same surgery, from 2011 to 2013, and that returned for controls 6–8 years later. All eyes improved their UCVA visual acuity and keratometric reading diminished from a mean of 54.3–51.6. No lines of BCVA were lost and 14 eyes gained two lines of vision (16.6%). 23 eyes gained one line (27.3%). No more Cross Linking was needed and some of those eyes returned successfully to wear contact lenses. Furthermore, when 17 eyes (20.2%) in these patients reached 20 years of age, and the complete stability of the defect was proved for more than 2 years and OCT showed enough stroma over the ring, a LASEK treatment was performed to further improve UCVA. From these, 13 eyes (76.4%) got complete independence to refractive correction.

The combination of PRK (photorefractive keratectomy) refractive treatment with the addition of Cross Linking has been the subject of many articles in the world literature [63, 64]. Although we have been working on PRK treatment of mild to moderate keratoconus since 1996, after 2006 we started combining them with Cross Linking. A very important paper from John Kanelopoulus [65], brought the term Athens Protocol to ophthalmology, that popularized this type of combined treatment soon after. Two papers have been published with our own results [66, 67].

We were able to retrieve 62 patients (95 eyes) with more than 10 years follow up from our practice. All eyes were treated for Lasik Ectasia (15 eyes) or keratoconus (77 eyes). The mean age was 25 (18–36 years). Our protocol for treatment is clearly stated in the papers in Dove Medical Press. The mean time for follow up was 10.3 years (from 9.7 to 12.4 years).

### *Keratoconus: A Treatable Disease DOI: http://dx.doi.org/10.5772/intechopen.101206*

### **Figure 2.**

*Corneal topography follow-up (year 2010–2019) of a pediatric 7 year old patient that had topography progression of the keratoconus. After corneal crosslinking Corneal topography shows keratometric and pachymetry stability in the right eye (upper maps) and in the left eye (lower maps).*

At the last visit results were as follows:


present in four eyes but cleared with time. One patient took over six months to complete the regression of the haze.

4.Most importantly, in the 10 years follow-up, only one eye required new application of Cross Linking three years after the first application due to increase of two diopters in the Kmax of the Pentacam. Patient admitted that eye rubbing was the cause, and it turned out to be the right eye of a right-handed patient. The other 98 eyes have been stable for this period!!

### **4. Conclusions**

With this chapter we have demonstrated several facts about keratoconus, that we can summarize as follows:


With this in mind, we make the following very strong statements as conclusions: **Keratoconus is no longer a disease without treatment**. Corneal transplant is no longer the only surgical option to correct keratoconus. The advent of Cross Linking a little more than 20 years ago, has not been a very well recognized advancement of the twenty-first century to Ophthalmology. Theo Seiler and his group gave one of the best gifts to the world, the option to make a person independent to the use of rigid contact lenses to see. It is our opinion, and one shared by many authors, that the time has come to free those patients of the contact lenses, and if complete freedom is not possible, at the very least improve their quality of life, allowing independence and use of better tolerated soft contact lenses or even glasses.

At the same time, we cannot tolerate young patients losing their 20/20 corrected visual acuity anymore. Patients have the right to receive Corneal Cross Linking to stop the advancement of the disease and improve their visual acuity at a later time.

The inherited regular astigmatism does not change after 10 years of age. We strongly encourage any ophthalmologist/optometrist involved in eye care to pay attention to children with an increased astigmatism over the years, and make sure they are not encountering a case of keratoconus. Today, several authors recommend the use of Cross Linking in any newly diagnosed case of keratoconus, regardless of the age and even without showing signs of progression. Even if this seems to be too

*Keratoconus: A Treatable Disease DOI: http://dx.doi.org/10.5772/intechopen.101206*

radical, it is important to at least be aware of the possibility of keratoconus and check the patient often with all the tests available today, and treat them if the possibility of losing the 20/20 correction comes to mind. The scientific literature does not cover the mistake of avoiding the use of this method to stop the progression of the keratoconus. Of course, preventing eye rubbing is also an important tool to help prevent the progression of the cone.

Furthermore, in the indicated cases, combination of Cross Linking with Wave Front or Topography guided Excimer Laser treatment, intrastromal rings or Intraocular lenses, have also been demonstrated to be safe and effective in improving quality of life of those patients.

Keep in mind: Keratoconus is a treatable disease.

### **Conflict of interest**

The authors declare no conflict of interest.

## **Author details**

Gustavo E. Tamayo\*, Eduardo J. Polania-Baron, Claudia Castell, Pilar Vargas and Juliana Tamayo Bogota Laser Ocular Surgery Center, Bogota D.C, Colombia

\*Address all correspondence to: centrogustavotamayo@gmail.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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### **Chapter 3**
